Ceftiofur, a semisynthetic cephalosporin, is a broad-spectrum antibiotic against both Gram-positive and Gram-negative bacteria including beta-lactamase-producing bacterial strains and anaerobes. Its antibacterial activity results from the inhibition of mucopeptide synthesis in the cell wall in a similar fashion to other cephalosporins. Ceftiofur is used in the treatment of respiratory infections in cattle and pigs. The chemical designation is 7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[2-furanylcarbonyl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. The sodium and hydrochloride salts are administered intramuscularly and intravenously.
Ceftiofur is first disclosed in U.S. Pat. No. 4,464,367, which also discloses a process for preparing Ceftiofur and its sodium salt.
U.S. Pat. No. 4,902,683 claims crystalline hydrochloride salt of Ceftiofur. According to this patent the conventional free acid and its sodium salt are unstable and are obtained as amorphous nature.
U.S. Pat. No. 5,721,359 claims a crystalline Ceftiofur free acid and a process for the preparation of the same.
U.S. Pat. No. 4,937,330 claims a process for the preparation of Ceftiofur sodium, though this patent mentioned the Ceftiofur sodium obtained according to this patent as a crystal form, this patent does not provide the X-ray diffraction pattern of the said crystal. According to this patent Ceftiofur sodium salt as isolated from aqueous tetrahydrofuran as a unique solid phase characterized by birefringent lath- and rod-shaped particles. However the x-ray diffraction of this unique gave no diffraction pattern. Moreover further treatment with a dry organic solvent (e.g., acetone or ethanol) produces solvent-free amorphous Ceftiofur sodium upon drying.
Hence all the prior art literature reported so far provide amorphous Ceftiofur sodium, and, owing to the amorphous nature, the conventional Ceftiofur sodium is less stable. Further, owing to the amorphous nature, purification is very difficult, and hence not preferable in industrial point of view.
The amorphous form of Ceftiofur salts such as sodium salt and amine salt and ester forms of this cephalosporin antibiotic are somewhat unstable chemically and are difficult to purify, and are less desirable to work with in manufacturing pharmaceutical formulations containing them. This amorphous salts are difficult solids to isolate in pure form and handle in pharmaceutical manufacturing plants. Hence there is a need to prepare Ceftiofur Sodium in a crystalline form.
WO 02/42266 claims a process for the production of Ceftiofur sodium treating the Ceftiofur hydrochloride with sodium source, separating sodium chloride using appropriate membrane (reverse osmosis technique to remove sodium chloride), and isolating Ceftiofur sodium by lyophilization.
U.S. Pat. No. 6,458,949 discloses a process in which after completion of cyclization with thiourea in example 1, sodium chloride was added into reaction mass, the resultant by-phasic layer was separated, followed by addition of sodium 2-ethyl hexonate to yield Ceftiofur sodium.
U.S. Pat. No. 6,555,680 discloses a process in which Ceftiofur sodium was prepared from Ceftiofur amine salt, however the complexity associated with work up procedure makes this process unfavorable for plant point of view.
Conventional process reported for the preparation of Ceftiofur sodium involves dissolution of Ceftiofur acid in a solvent like acetone, methanol, THF, water or mixtures thereof using an organic amine followed by the addition of sodium salt of weak acid like sodium 2-ethyl hexonate or neutralizing the Ceftiofur hydro halide salt with sodium ion source followed by converting the acid into Ceftiofur sodium by using membrane filtration.
In our continued research we have identified a process for the preparation of Ceftiofur sodium as a crystalline product, the crystalline Ceftiofur sodium prepared according to our invention is novel and having good stability over conventional amorphous product. None of the prior art suggests or event motivates the present invention.